Organogenesis and tissue homeostasis within the gastrointestinal (GI) tract require continuous crosstalk between the endodermal epithelium and adjacent mesenchyme. Much of what is known about GI development has been learned from studies of the endoderm and its derivatives; however, little is known about the genetic and cellular mechanisms governing gut mesenchymal development. This grant application is designed to uncover the mechanisms that underlie this important, yet poorly understood developmental system. The proposed studies are centered on charactering on the molecular basis of growth and patterning in the gut mesenchyme. We will use a combination of mouse genetics and cellular approaches to address three principle questions. First, we will define a Sox-dependent molecular switch that is responsible for coordinating early primitive progenitor expansion and subsequent mesenchymal differentiation. In the second part of the grant, we will identify the signaling pathways that act in concert to control smooth muscle growth and intestinal organ size. In the third part of the grant, we will explore a novel mesenchymal mechanism that is involved in suppression of intestinal polyposis. We believe that completion of the proposed studies will significantly further our understanding of the fundamental mechanisms controlling gut development and homeostasis. This knowledge gained from our studies will ultimately contribute to the development of new therapies for treating GI-related diseases and cancers.